Pharmaceutical composition

ABSTRACT

A pharmaceutical composition is described. The composition comprises: (i) a drug component consisting of salmeterol xinafoate and fluticasone propionate. and (ii) a propellant component at least 90 wt % of which is 1,1-difluoroethane (HFA-152a). The drug component is the sole drug component in the pharmaceutical composition.

This application is a continuation of U.S. patent application Ser. No.16/882,979, filed May 26, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/334,144, filed Mar. 18, 2019, which is the U.S.National Phase under 35 U.S.C. § 371 of International Application No.PCT/GB2017/052764, filed Sep. 18, 2017, designating the United Statesand published in English on Mar. 22, 2018, as WO 2018/051133, whichclaims priority to United Kingdom Application No. 1615914.7, filed Sep.19, 2016 and to United Kingdom Application No. 1620517.1, filed Dec. 2,2016, each of which is incorporated by reference in its entirety.

FIELD

The present invention relates to the delivery of drug formulations froma medical device, such as a metered dose inhaler (MDI), using apropellant comprising 1,1-difluoroethane (HFA-152a). More particularly,the present invention relates to pharmaceutical compositions comprisingHFA-152a propellant and a drug formulation which is dissolved orsuspended in the propellant and to medical devices containing thosecompositions. The pharmaceutical compositions of the invention areparticularly suited for delivery from a pressurised aerosol containerusing a metered dose inhaler (MDI).

BACKGROUND

MDIs are the most significant type of inhalation drug delivery systemand are well known to those skilled in the art. They are designed todeliver, on demand, a discrete and accurate amount of a drug to therespiratory tract of a patient using a liquefied propellant in which thedrug is dissolved, suspended or dispersed. The design and operation ofMDIs is described in many standard textbooks and in the patentliterature. They all comprise a pressurised container that holds thedrug formulation, a nozzle and a valve assembly that is capable ofdispensing a controlled quantity of the drug through the nozzle when itis activated. The nozzle and valve assembly are typically located in ahousing that is equipped with a mouth piece. The drug formulation willcomprise a propellant, in which the drug is dissolved, suspended ordispersed, and may contain other materials such as polar excipients,surfactants and preservatives.

In order for a propellant to function satisfactorily in MDIs, it needsto have a number of properties. These include an appropriate boilingpoint and vapour pressure so that it can be liquefied in a closedcontainer at room temperature but develop a high enough pressure whenthe MDI is activated to deliver the drug as an atomised formulation evenat low ambient temperatures. Further, the propellant should be of lowacute and chronic toxicity and have a high cardiac sensitisationthreshold. It should have a high degree of chemical stability in contactwith the drug, the container and the metallic and non-metalliccomponents of the MDI device, and have a low propensity to extract lowmolecular weight substances from any elastomeric materials in the MDIdevice. The propellant should also be capable of maintaining the drug ina homogeneous solution, in a stable suspension or in a stable dispersionfor a sufficient time to permit reproducible delivery of the drug inuse. When the drug is in suspension in the propellant, the density ofthe liquid propellant is desirably similar to that of the solid drug inorder to avoid rapid sinking or floating of the drug particles in theliquid. Finally, the propellant should not present a significantflammability risk to the patient in use. In particular, it should form anon-flammable or low flammability mixture when mixed with air in therespiratory tract.

Dichlorodifluoromethane (R-12) possesses a suitable combination ofproperties and was for many years the most widely used MDI propellant,often blended with trichlorofluoromethane (R-11). Due to internationalconcern that fully and partially halogenated chlorofluorocarbons (CFCs),such as dichlorodifluoromethane and trichlorofluoromethane, weredamaging the earth's protective ozone layer, many countries entered intoan agreement, the Montreal Protocol, stipulating that their manufactureand use should be severely restricted and eventually phased outcompletely. Dichlorodifluoromethane and trichlorofluoromethane werephased out for refrigeration use in the 1990's, but are still used insmall quantities in the MDI sector as a result of an essential useexemption in the Montreal Protocol.

1,1,1,2-tetrafluoroethane (HFA-134a) was introduced as a replacementrefrigerant and MDI propellant for R-12.1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) was also introduced as areplacement propellant for dichlorotetrafluoroethane (R-114) in the MDIsector and is sometimes used alone or blended with HFA -134a for thisapplication.

Although HFA-134a and HFA-227ea have low ozone depletion potentials(ODPs), they have global warming potentials (GWPs), 1430 and 3220respectively, which are now considered to be too high by some regulatorybodies, especially for dispersive uses when they are released into theatmosphere.

One industrial area that has received particular attention recently hasbeen the automotive air-conditioning sector where the use of HFA-134ahas come under regulatory control as a result of the European Mobile AirConditioning Directive (2006/40/EC). Industry is developing a number ofpossible alternatives to HFA-134a in automotive air conditioning andother applications that have a low greenhouse warming potential (GWP) aswell as a low ozone depletion potential (ODP). Many of thesealternatives include hydrofluoropropenes, especially thetetrafluoropropenes, such as 2,3,3,3-tetrafluoropropene (HFO-1234yf) and1,3,3,3-tetrafluoropropene (HFO-1234ze).

Although the proposed alternatives to HFA-134a have a low GWP, thetoxicological status of many of the components, such as certain of thefluoropropenes, is unclear and they are unlikely to be acceptable foruse in the MDI sector for many years, if at all.

Salmeterol and salmeterol xinafoate are long acting beta-2-agonists(LABA) used in the treatment and control of a number ofrespiratory-related disorders, but particularly asthma and chronicobstructive pulmonary disease (CORD). Both drugs are convenientlydelivered using a MDI. Whilst salmeterol treatment is very effective,the performance of salmeterol in many of these therapies may be improvedby administration in combination with a corticosteroid, such as theglucocorticoid steroid fluticasone.

There is a need for a salmeterol-based pharmaceutical composition whichcan be delivered using a MDI and that uses a propellant having a reducedGWP in comparison with HFA-134a and HFA-227ea. There is also a need fora salmeterol-based pharmaceutical composition which exhibits improvedstability.

DETAILED DESCRIPTION

We have found that a propellant comprising 1,1-difluoroethane (HFA-152a)can be used to successfully deliver salmeterol-based drug formulationsusing a MDI. These formulations can exhibit improved chemical stability,particularly where the formulations contain low amounts of water,improved aerosolisation performance for improved drug delivery, goodsuspension stability, reduced GWP, good compatibility with standarduncoated aluminium cans as well as good compatibility with standardvalves and seals.

According to a first aspect of the present invention, there is provideda pharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   -   (i) a drug component comprising at least one salmeterol compound        selected from salmeterol and the pharmaceutically acceptable        derivatives thereof, especially the pharmaceutically acceptable        salts thereof; and    -   (ii) a propellant component comprising 1,1-difluoroethane        (HFA-152a).

The pharmaceutical composition of the first aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. The improved chemical stability isobserved, in particular, when the pharmaceutical composition containsless than 100 ppm, preferably less than 50 ppm, more preferably lessthan 10 ppm and particularly less than 5 ppm of water based on the totalweight of the pharmaceutical composition. In referring to the watercontent of the pharmaceutical composition, we are referring to thecontent of free water in the composition and not any water that happensto be present in any hydrated drug compounds that may be used as part ofthe drug component. In an especially preferred embodiment, thepharmaceutical composition is water-free. Alternatively, thepharmaceutical composition of the first aspect may contain greater than0.5 ppm of water, e.g.

greater than 1 ppm, but less than the amounts discussed above, as it canin practice be difficult to remove all the water from the compositionand then retain it in such a water-free state.

Accordingly a preferred embodiment of the first aspect of the presentinvention provides a pharmaceutical composition, e.g. a pharmaceuticalsuspension or a pharmaceutical solution, said composition comprising:

-   -   (i) a drug component comprising at least one salmeterol compound        selected from salmeterol and the pharmaceutically acceptable        derivatives thereof, especially the pharmaceutically acceptable        salts thereof; and    -   (ii) a propellant component comprising 1,1-difluoroethane        (HFA-152a), wherein the composition contains less than 100 ppm,        preferably less than 50 ppm, more preferably less than 10 ppm        and especially less than 5 ppm of water based on the total        weight of the pharmaceutical composition.

In a preferred embodiment, the pharmaceutical composition of the firstaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the first aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Accordingly a preferred embodiment of the first aspect of the presentinvention provides a pharmaceutical composition, e.g. a pharmaceuticalsuspension or a pharmaceutical solution, said composition comprising:

-   -   (i) a drug component comprising at least one salmeterol compound        selected from salmeterol and the pharmaceutically acceptable        derivatives thereof, especially the pharmaceutically acceptable        salts thereof; and    -   (ii) a propellant component comprising 1,1-difluoroethane        (HFA-152a), wherein the composition contains less than 1000 ppm,        preferably less than 500 ppm, more preferably less than 100 ppm        and especially less than 50 ppm of oxygen based on the total        weight of the pharmaceutical composition.

The pharmaceutical composition of the present invention is suitable fordelivery to the respiratory tract using a metered dose inhaler (MDI).

The at least one salmeterol compound in the pharmaceutical compositionof the invention in all aspects and embodiments disclosed herein ispreferably in a micronized form. Further, the pharmaceutical compositionof the invention in all aspects and embodiments disclosed herein ispreferably free of perforated microstructures.

The at least one salmeterol compound may be dispersed or suspended inthe propellant. The drug particles in such suspensions preferably have adiameter of less than 100 microns, e.g. less than 50 microns. However,in an alternative embodiment the pharmaceutical compositions of theinvention are solutions with the at least one salmeterol compounddissolved in the propellant, e.g. with the assistance of a polarexcipient, such as ethanol.

Suitable pharmaceutically acceptable derivatives of salmeterol include,inter alia, pharmaceutically acceptable salts, pharmaceuticallyacceptable prodrugs, pharmaceutically acceptable solvates,pharmaceutically acceptable hydrates, pharmaceutically acceptableesters, solvates of pharmaceutically acceptable salts, solvates ofpharmaceutically acceptable prodrugs, hydrates of pharmaceuticallyacceptable salts and hydrates of pharmaceutically acceptable prodrugs. Apreferred pharmaceutically acceptable derivative of salmeterol is apharmaceutically acceptable salt thereof, particularly salmeterolxinafoate. In a particularly preferred embodiment, the at least onesalmeterol compound in the pharmaceutical composition of the firstaspect of the invention is salmeterol or salmeterol xinafoate,especially salmeterol xinafoate.

The amount of the drug component in the pharmaceutical composition ofthe first aspect of the present invention will typically be in the rangeof from 0.01 to 2.5 weight % based on the total weight of thepharmaceutical composition. Preferably, the drug component will comprisefrom 0.01 to 2.0 weight %, more preferably from 0.05 to 2.0 weight % andespecially from 0.05 to 1.5 weight % of the total weight of thepharmaceutical composition. The drug component may consist essentiallyof or consist entirely of the at least one salmeterol compound selectedfrom salmeterol and the pharmaceutically acceptable derivatives thereof.By the term “consists essentially of”, we mean that at least 98 weight%, more preferably at least 99 weight % and especially at least 99.9weight % of the drug component consists of the least one salmeterolcompound. Alternatively, the drug component may contain other drugs,such as at least one corticosteroid and/or least one long actingmuscarinic antagonist (LAMA).

The propellant component in the pharmaceutical composition of the firstaspect of the present invention comprises 1,1-difluoroethane (HFA-152a).Thus, we do not exclude the possibility that the propellant componentmay include other propellant compounds in addition to the HFA-152a. Forexample, the propellant component may additionally comprise one or moreadditional hydrofluorocarbon or hydrocarbon propellant compounds, e.g.selected from HFA-227ea, HFA-134a, difluoromethane (HFA-32), propane,butane, isobutane and dimethyl ether. The preferred additionalpropellants are HFA-227ea and HFA-134a.

If an additional propellant compound is included, such as HFA-134a orHFA-227ea, at least 5% by weight, preferably at least 10% by weight andmore preferably at least 50% by weight of the propellant componentshould be HFA-152a. Typically, the HFA-152a will constitute at least 90weight %, e.g. from 90 to 99 weight %, of the propellant component.Preferably, the HFA-152a will constitute at least 95 weight %, e.g. from95 to 99 weight %, and more preferably at least 99 weight of thepropellant component.

In a preferred embodiment, the propellant component has a global warmingpotential (GWP) of less than 250, more preferably less than 200 andstill more preferably less than 150.

In an especially preferred embodiment, the propellant component consistsentirely of HFA-152a so that the pharmaceutical composition of theinvention comprises HFA-152a as the sole propellant. By the term“consists entirely of” we do not, of course, exclude the presence ofminor amounts, e.g. up to a few hundred parts per million, of impuritiesthat may be present following the process that is used to make theHFA-152a providing that they do not affect the suitability of thepropellant in medical applications. Preferably the HFA-152a propellantwill contain no more than 10 ppm, e.g. from 0.5 to 10 ppm, morepreferably no more than 5 ppm, e.g. from 1 to 5 ppm, of unsaturatedimpurities, such as vinyl fluoride, vinyl chloride, vinylidene fluorideand chloro-fluoro ethylene compounds.

The amount of propellant component in the pharmaceutical composition ofthe invention will vary depending on the amounts of the drugs and othercomponents in the pharmaceutical composition. Typically, the propellantcomponent will comprise from 80.0 to 99.99 weight % of the total weightof the pharmaceutical composition. Preferably, the propellant componentwill comprise from 90.0 to 99.99 weight %, more preferably from 96.5 to99.99 weight % and especially from 97.5 to 99.95 weight % of the totalweight of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition of the first aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the firstaspect of the present invention additionally includes a polar excipient,such as ethanol. Polar excipients have been used previously inpharmaceutical compositions for treating respiratory disorders that aredelivered using metered dose inhalers (MDIs). They are also referred toas solvents, co-solvents, carrier solvents and adjuvants. Theirinclusion can serve to solubilise the surfactant or the drug in thepropellant and/or inhibit deposition of drug particles on the surfacesof the metered dose inhaler that are contacted by the pharmaceuticalcomposition as it passes from the container in which it is stored to thenozzle outlet. They are also used as bulking agents in two-stage fillingprocesses where the drug is mixed with a suitable polar excipient.

The most commonly used polar excipient is ethanol. If a polar excipientis used, it will typically be present in an amount of from 0.5 to 10% byweight, preferably in an amount of from 1 to 5 % by weight based on thetotal weight of the pharmaceutical composition.

In one preferred embodiment, the pharmaceutical composition of thepresent invention is free of polar excipients such as ethanol.

The pharmaceutical composition of the first aspect of the presentinvention may also include a surfactant component comprising at leastone surfactant compound.

Where the pharmaceutical composition is a suspension, the surfactantcomponent is preferably not present as a surface coating on the drugparticles. Drug particles with such surface coatings are prepared bypre-coating the drug particles with the surfactant component prior tomixing with the propellant component.

Surfactant compounds of the type that have been in use hitherto inpharmaceutical formulations for MDIs may be used in the pharmaceuticalcompositions of the present invention. Preferred surfactants areselected from polyvinylpyrrolidone, polyethylene glycol surfactants,oleic acid and lecithin. By the term oleic acid, we are not necessarilyreferring to pure (9Z)-octadec-9-enoic acid. When sold for surfactantuse in medical applications, oleic acid is typically a mixture ofseveral fatty acids, with (9Z)-octadec-9-enoic acid being thepredominant fatty acid, e.g. present in an amount of at least 65 weight% based on the total weight of the surfactant.

If a surfactant component is included, it is preferably free offluorinated surfactant compounds. In another embodiment, the surfactantcomponent is free of surfactant compounds selected from C₈₋₁₆ fattyacids or salts, bile salts, phospholipids and alkyl saccharides.

In a preferred embodiment, the surfactant component consists essentiallyof and still more preferably consists entirely of at least onesurfactant compound selected from polyvinylpyrrolidone, polyethyleneglycols, oleic acid and lecithin. In a particularly preferredembodiment, the surfactant component consists essentially of and stillmore preferably consists entirely of at least one surfactant compoundselected from polyvinylpyrrolidone and polyethylene glycols. By the term“consists essentially or”, we mean that at least 95 weight %, morepreferably at least 98 weight % and especially at least 99 weight % ofthe surfactant component is composed of the listed surfactants.

If a surfactant component is used, it will typically be present in anamount of from 0.1 to 2.5% by weight, preferably in an amount of from0.2 to 1.5% by weight based on the total weight of the pharmaceuticalcomposition.

The pharmaceutical composition of the invention may also include a longacting muscarinic antagonist (LAMA). Any of the long acting muscarinicantagonists that have been in use hitherto for treating chronicobstructive pulmonary diseases and that can be delivered using a MDI canbe used in the pharmaceutical compositions of the present invention.Suitable long acting muscarinic antagonists include umeclidinium,ipratropium, tiotropium, aclidinium and the pharmaceutically acceptablederivatives thereof, especially the pharmaceutically acceptable saltsthereof. Preferred compounds include the pharmaceutically acceptablesalts of glycopyrrolate (also known as glycopyrronium). Glycopyrrolateis a quaternary ammonium salt. Suitable pharmaceutically acceptablecounter ions include, for example, fluoride, chloride, bromide, iodide,nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate,propionate, butyrate, lactate, citrate, tartrate, malate, maleate,succinate, benzoate, p-chlorobenzoate, diphenyl-acetate ortriphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate,1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate,methanesulfonate and benzenesulfonate. A preferred compound is thebromide salt of glycopyrrolate also known as glycopyrronium bromide.

According to a second aspect of the present invention, there is provideda pharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   -   (i) a drug component comprising at least one salmeterol compound        selected from salmeterol and the pharmaceutically acceptable        derivatives thereof, especially the pharmaceutically acceptable        salts thereof and at least one long acting muscarinic        antagonist, particularly at least one pharmaceutically        acceptable salt of glycopyrrolate; and    -   (ii) a propellant component comprising 1,1-difluoroethane        (HFA-152a).

The pharmaceutical composition of the second aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. Preferably, the pharmaceuticalcomposition of the second aspect of the invention contains less than 100ppm, more preferably less than 50 ppm, particularly less than 10 ppm andespecially less than 5 ppm of water based on the total weight of thepharmaceutical composition. It has been found that small amounts ofwater alongside the use of HFA-152a as the propellant can result in apharmaceutical composition with improved chemical stability. Inreferring to the water content of the pharmaceutical composition, we arereferring to the content of free water in the composition and not anywater that happens to be present in any hydrated drug compounds that maybe used as part of the drug component. In an especially preferredembodiment, the pharmaceutical composition of the second aspect of thepresent invention is water-free. Alternatively, the pharmaceuticalcomposition of the second aspect may contain greater than 0.5 ppm ofwater, e.g. greater than 1 ppm, but less than the amounts discussedabove, as it can in practice be difficult to remove all the water fromthe composition and then retain it in such a water-free state.

In a preferred embodiment, the pharmaceutical composition of the secondaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the second aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Suitable and preferred salmeterol compounds are as discussed above forthe pharmaceutical composition of the first aspect of the presentinvention.

Typical and preferred amounts of the drug component and the propellantcomponent in the pharmaceutical composition of the second aspect of thepresent invention and suitable, typical and preferred compositions forthe propellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. The drug component mayconsist essentially of or consist entirely of the at least onesalmeterol compound and the at least one long acting muscarinicantagonist. By the term “consists essentially of”, we mean that at least98 weight %, more preferably at least 99 weight % and especially atleast 99.9 weight % of the drug component consists of the at least onesalmeterol compound and the at least one long acting muscarinicantagonist.

In one embodiment, the pharmaceutical composition of the second aspectof the present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the secondaspect of the invention may contain one or both of a polar excipient anda surfactant component as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. Suitable and preferredpolar excipients and surfactants are as discussed above for thepharmaceutical composition of the first aspect of the invention. Typicaland preferred amounts of the polar excipient and the surfactantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

In an especially preferred embodiment of the second aspect of theinvention, the drug component comprises at least one salmeterol compoundselected from salmeterol and salmeterol xinafoate and at least onepharmaceutically acceptable salt of glycopyrrolate, especiallyglycopyrronium bromide. Preferably, the at least one selected salmeterolcompound and the at least one selected pharmaceutically acceptable saltof glycopyrrolate are the only pharmaceutical actives in thepharmaceutical composition of the second aspect of the invention.

The pharmaceutical composition of the invention may also include acorticosteroid. Any of the corticosteroids that have been in usehitherto for treating asthma and chronic obstructive pulmonary diseasesand that can be delivered using a MDI can be used in the pharmaceuticalcompositions of the present invention. Suitable corticosteroids includebudesonide, mometasone, beclomethasone and fluticasone as well as theirpharmaceutically acceptable derivatives, such as their pharmaceuticallyacceptable salts and esters. Preferred compounds include fluticasone andfluticasone propionate.

Accordingly, a third aspect of the present invention provides apharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   -   (i) a drug component comprising at least one salmeterol compound        selected from salmeterol and the pharmaceutically acceptable        derivatives thereof, especially the pharmaceutically acceptable        salts thereof and at least one corticosteroid, particularly at        least one corticosteroid selected from fluticasone, budesonide,        mometasone and beclomethasone and the pharmaceutically        acceptable derivatives thereof, especially fluticasone and        fluticasone propionate; and    -   (ii) a propellant component comprising 1,1-difluoroethane        (HFA-152a).

The pharmaceutical composition of the third aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. Preferably, the pharmaceuticalcomposition of the third aspect of the invention contains less than 100ppm, more preferably less than 50 ppm, particularly less than 10 ppm andespecially less than 5 ppm of water based on the total weight of thepharmaceutical composition. It has been found that small amounts ofwater alongside the use of HFA-152a as the propellant can result in apharmaceutical composition with improved chemical stability. Inreferring to the water content of the pharmaceutical composition, we arereferring to the content of free water in the composition and not anywater that happens to be present in any hydrated drug compounds that maybe used as part of the drug component. In an especially preferredembodiment, the pharmaceutical composition of the third aspect of thepresent invention is water-free. Alternatively, the pharmaceuticalcomposition of the third aspect may contain greater than 0.5 ppm ofwater, e.g. greater than 1 ppm, but less than the amounts discussedabove, as it can in practice be difficult to remove all the water fromthe composition and then retain it in such a water-free state.

In a preferred embodiment, the pharmaceutical composition of the thirdaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the third aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Suitable and preferred salmeterol compounds are as discussed above forthe pharmaceutical composition of the first aspect of the presentinvention.

Typical and preferred amounts of the drug component and the propellantcomponent in the pharmaceutical composition of the third aspect of thepresent invention and suitable, typical and preferred compositions forthe propellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. The drug component mayconsist essentially of or consist entirely of the at least onesalmeterol compound and the at least one corticosteroid. By the term“consists essentially of”, we mean that at least 98 weight %, morepreferably at least 99 weight % and especially at least 99.9 weight % ofthe drug component consists of the at least one salmeterol compound andthe at least one corticosteroid.

In one embodiment, the pharmaceutical composition of the third aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the thirdaspect of the invention may contain one or both of a polar excipient anda surfactant component as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. Suitable and preferredpolar excipients and surfactants are as discussed above for thepharmaceutical composition of the first aspect of the invention. Typicaland preferred amounts of the polar excipient and the surfactantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

In an especially preferred embodiment of the third aspect of theinvention, the drug component comprises at least one salmeterol compoundselected from salmeterol and salmeterol xinafoate and fluticasonepropionate. Preferably, the at least one selected salmeterol compoundand the fluticasone propionate are the only pharmaceutical actives inthe pharmaceutical composition of the third aspect of the invention.

The pharmaceutical composition of the invention may also include a longacting muscarinic antagonist (LAMA) and a corticosteroid. Any of thelong acting muscarinic antagonists and corticosteroids that have been inuse hitherto for treating asthma and chronic obstructive pulmonarydiseases and that can be delivered using a MDI can be used in thepharmaceutical compositions of the present invention. Suitable andpreferred long acting muscarinic antagonists are as discussed above forthe second aspect of the invention. Suitable and preferredcorticosteroids are as discussed above for the third aspect of thepresent invention.

Accordingly, a fourth aspect of the present invention provides apharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   -   (i) a drug component comprising at least one salmeterol compound        selected from salmeterol and the pharmaceutically acceptable        derivatives thereof, especially the pharmaceutically acceptable        salts thereof, at least one long acting muscarinic antagonist,        particularly at least one pharmaceutically acceptable salt of        glycopyrrolate, and at least one corticosteroid, particularly at        least one corticosteroid selected from fluticasone, budesonide,        mometasone and beclomethasone and the pharmaceutically        acceptable derivatives thereof, especially fluticasone and        fluticasone propionate; and    -   (ii) a propellant component comprising 1,1-difluoroethane        (HFA-152a).

The pharmaceutical composition of the fourth aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. Preferably, the pharmaceuticalcomposition of the fourth aspect of the present invention contains lessthan 100 ppm, more preferably less than 50 ppm, particularly less than10 ppm and especially less than 5 ppm of water based on the total weightof the pharmaceutical composition. It has been found that small amountsof water alongside the use of HFA-152a as the propellant can result in apharmaceutical composition with improved chemical stability. Inreferring to the water content of the pharmaceutical composition, we arereferring to the content of free water in the composition and not anywater that happens to be present in any hydrated drug compounds that maybe used as part of the drug component. In an especially preferredembodiment, the pharmaceutical composition of the fourth aspect of thepresent invention is water-free. Alternatively, the pharmaceuticalcomposition of the fourth aspect may contain greater than 0.5 ppm ofwater, e.g. greater than 1 ppm, but less than the amounts discussedabove, as it can in practice be difficult to remove all the water fromthe composition and then retain it in such a water-free state.

In a preferred embodiment, the pharmaceutical composition of the fourthaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the fourth aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Suitable and preferred salmeterol compounds are as discussed above forthe pharmaceutical composition of the first aspect of the presentinvention.

Typical and preferred amounts of the drug component and the propellantcomponent in the pharmaceutical composition of the fourth aspect of thepresent invention and suitable, typical and preferred compositions forthe propellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. The drug component mayconsist essentially of or consist entirely of the at least onesalmeterol compound, the at least one long acting muscarinic antagonist(LAMA) and the at least one corticosteroid. By the term “consistsessentially of”, we mean that at least 98 weight %, more preferably atleast 99 weight % and especially at least 99.9 weight % of the drugcomponent consists of the at least one salmeterol compound, the at leastone long acting muscarinic antagonist (LAMA) and the at least onecorticosteroid.

In one embodiment, the pharmaceutical composition of the fourth aspectof the present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the fourthaspect of the invention may contain one or both of a polar excipient anda surfactant component as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. Suitable and preferredpolar excipients and surfactants are as discussed above for thepharmaceutical composition of the first aspect of the invention. Typicaland preferred amounts of the polar excipient and the surfactantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

In an especially preferred embodiment of the fourth aspect of theinvention, the drug component comprises at least one salmeterol compoundselected from salmeterol and salmeterol xinafoate, at least onepharmaceutically acceptable salt of glycopyrrolate, especiallyglycopyrronium bromide, and fluticasone propionate. Preferably, the atleast one selected salmeterol compound, the at least onepharmaceutically acceptable salt of glycopyrrolate and the fluticasonepropionate are the only pharmaceutical actives in the pharmaceuticalcomposition of the fourth aspect of the invention.

Preferably, the pharmaceutical compositions of the present disclosureare free of polymers having amide and/or carboxylic acid ester repeatingstructural units.

It has been found that the use of propellants comprising1,1-difluoroethane (HFA-152a) in pharmaceutical compositions containinga salmeterol compound, such as salmeterol xinafoate, and the propellantcan unexpectedly improve the chemical stability of the salmeterolcompound compared to the stability it exhibits in formulationscontaining either HFA-134a or HFA-227ea as the propellant.

Accordingly, in a fifth aspect of the present invention there isprovided a method of improving the stability of a pharmaceuticalcomposition comprising a propellant component and a drug componentcomprising at least one salmeterol compound selected from salmeterol andthe pharmaceutically acceptable derivatives thereof, said methodcomprising using a propellant component comprising 1,1-difluoroethane(HFA-152a).

The pharmaceutical composition in the stabilisation method of the fifthaspect of the present invention may be a suspension or a solution.

The improved chemical stability can result, in particular, when thepharmaceutical composition contains less than 500 ppm, preferably lessthan 100 ppm, more preferably less than 50 ppm, still more preferablyless than 10 ppm and particularly less than 5 ppm of water based on thetotal weight of the pharmaceutical composition. In referring to thewater content of the pharmaceutical composition, we are referring to thecontent of free water in the composition and not any water that happensto be present in any hydrated drug compounds that may be used as part ofthe drug component. In an especially preferred embodiment, thepharmaceutical composition is water-free. Alternatively, thepharmaceutical composition recited in the fifth aspect of the presentinvention may contain greater than 0.5 ppm of water, e.g. greater than 1ppm, but less than the amounts discussed above, as it can in practice bedifficult to remove all the water from the composition and then retainit in such a water-free state.

Accordingly, in a preferred embodiment of the fifth aspect of thepresent invention there is provided a method of improving the stabilityof a pharmaceutical composition comprising a propellant component and adrug component comprising at least one salmeterol compound selected fromsalmeterol and the pharmaceutically acceptable derivatives thereof, saidmethod comprising using a propellant component comprising1,1-difluoroethane (HFA-152a) and selecting the components andconditions for the preparation of the pharmaceutical composition tomaintain the water content of the pharmaceutical composition below 100ppm, preferably below 50 ppm, more preferably below 10 ppm andparticularly below 5 ppm based on the total weight of the pharmaceuticalcomposition.

In practice, preparing a pharmaceutical composition with the low waterlevels recited above involves using a propellant component with asuitably low water content, as it is usually the largest mass item inthe finished device, and then preparing the pharmaceutical compositionunder suitably dry conditions, e.g. in a dry nitrogen atmosphere.Preparing pharmaceutical compositions under dry conditions is well knownand the techniques involved are well understood by those skilled in theart. Other steps to obtain a low water content in the finished deviceinclude drying and storing the can and valve components in amoisture-controlled atmosphere, e.g. dry nitrogen or air, prior to andduring device assembly. If the pharmaceutical composition contains asignificant amount of ethanol, then it may also be important to controlthe water content of the ethanol as well as the propellant, e.g. bydrying to reduce the water content to suitably low levels. Suitabledrying techniques are well known to those skilled in the art and includethe use of a molecular sieve or other inorganic desiccant and membranedrying processes.

In the stabilisation method of the fifth aspect of the present inventionsuitable and preferred salmeterol compounds and derivatives thereof areas described above for the pharmaceutical composition of the firstaspect of the present invention. In addition, typical and preferredamounts of the drug component and the propellant component in thestabilisation method of the fifth aspect of the present invention andsuitable, typical and preferred compositions for the propellantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

The drug component in the stabilisation method of the fifth aspect ofthe present invention may consist essentially of or consist entirely ofthe at least one salmeterol compound selected from salmeterol and thepharmaceutically acceptable derivatives thereof. By the term “consistsessentially of”, we mean that at least 98 weight %, more preferably atleast 99 weight % and especially at least 99.9 weight % of the drugcomponent consists of the least one salmeterol compound. Alternatively,the drug component may additionally comprise at least one long actingmuscarinic antagonist and/or at least one corticosteroid. When a longacting muscarinic antagonist and/or a corticosteroid are included,suitable and preferred long acting muscarinic antagonists and suitableand preferred corticosteroids are as described above for thepharmaceutical compositions of the second and third aspects of thepresent invention.

In one embodiment, the pharmaceutical composition in the fifth aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the drug component and the propellant component asdefined above. By the term “consists essentially of”, we mean that atleast 98 weight %, more preferably at least 99 weight % and especiallyat least 99.9 weight % of the pharmaceutical composition consists of thetwo components.

In an alternative embodiment, the pharmaceutical composition in thefifth aspect of the invention may contain one or both of a polarexcipient and a surfactant component as discussed above for thepharmaceutical composition of the first aspect of the invention.Suitable and preferred polar excipients and surfactants are as discussedabove for the pharmaceutical composition of the first aspect of theinvention. Typical and preferred amounts of the polar excipient and thesurfactant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

In one preferred stabilisation method, the resulting pharmaceuticalcomposition after storage at 40° C. and 75% relative humidity for 6months will produce less than 0.4% by weight and preferably less than0.36% by weight of impurities from the degradation of the at least onesalmeterol compound based on the total weight of the at least onesalmeterol compound and the impurities.

In another preferred stabilisation method in which the pharmaceuticalcomposition also comprises at least one corticosteroid and/or at leastone long acting muscarinic antagonist, the resulting pharmaceuticalcomposition after storage at 40° C. and 75% relative humidity for 6months will produce less than 0.4% by weight and preferably less than0.36% by weight of impurities from the degradation of the at least onesalmeterol compound based on the total weight of the at least onesalmeterol compound and the impurities.

In yet another preferred stabilisation method, at least 97.5% by weight,preferably at least 98.0% by weight and more preferably at least 98.5%by weight of the at least one salmeterol compound that is containedoriginally in the pharmaceutical composition immediately followingpreparation will be present in the composition after storage at 40° C.and 75% relative humidity for 6 months.

In still another preferred stabilisation method in which thepharmaceutical composition also comprises at least one corticosteroidand/or at least one long acting muscarinic antagonist, at least 97.5% byweight, preferably at least 98.0% by weight and more preferably at least98.5% by weight of the at least one salmeterol compound that iscontained originally in the pharmaceutical composition immediatelyfollowing preparation will be present in the composition after storageat 40° C. and 75% relative humidity for 6 months.

In a further preferred stabilisation method, at least 97.5%, preferablyat least 98.0% and more preferably at least 98.5% of the originalpharmaceutical activity of the composition is retained after storage at40° C. and 75% relative humidity for 6 months.

One preferred pharmaceutical composition of the first, second, third andfourth aspects of the present invention will produce less than 0.4% byweight and preferably less than 0.36% by weight of total impurities fromthe degradation of the at least one salmeterol compound after storage at40° C. and 75% relative humidity for 6 months.

The weight % of impurities indicated above are based on the total weightof the at least one salmeterol compound and the impurities.

In a further preferred pharmaceutical composition of the first, second,third and fourth aspects of the present invention at least 97.5% byweight, preferably at least 98.0% by weight and more preferably at least98.5% by weight of the at least one salmeterol compound that iscontained originally in the pharmaceutical composition of the inventionimmediately following preparation will be present in the compositionafter storage at 40° C. and 75% relative humidity for 6 months.

In yet another preferred pharmaceutical composition of the first,second, third and fourth aspects of the present invention at least97.5%, preferably at least 98.0% and more preferably at least 98.5% ofthe original pharmaceutical activity of the pharmaceutical compositionof the invention is retained after storage at 40° C. and 75% relativehumidity for 6 months.

In referring to the storage of the pharmaceutical compositions in theabove described stabilisation methods, we are referring, in particular,to the storage of those compositions in uncoated aluminium containers.Similarly, in referring to the storage of the above describedpharmaceutical compositions, we are referring, in particular, to theirstorage in uncoated aluminium containers.

It has been found that the use of propellants comprising1,1-difluoroethane (HFA-152a) in pharmaceutical compositions containinga salmeterol compound, such as salmeterol xinafoate, and the propellantthat are designed to be delivered using a metered dose inhaler canunexpectedly improve the aerosolization performance of thepharmaceutical composition when that composition is delivered from themetered dose inhaler compared to the performance that is observed wheneither HFA-134a or HFA-227ea is used as the propellant. In particular,the fine particle fraction of the salmeterol compound in the emitteddose typically comprises at least 40 weight %, preferably at least 42.5weight % and more preferably at least 45 weight % of the emitted dose ofthe salmeterol compound. We are referring here, in particular, to theemitted dose that is observed immediately after the pharmaceuticalcomposition has been filled into a MDI canister and prior to any longterm storage.

Accordingly, in a sixth aspect of the present invention there isprovided a method of improving the aerosolization performance of apharmaceutical composition comprising a propellant component and a drugcomponent comprising at least one salmeterol compound selected fromsalmeterol and the pharmaceutically acceptable derivatives thereof, saidmethod comprising using a propellant component comprising1,1-difluoroethane (HFA-152a).

The pharmaceutical composition in the method of the sixth aspect of thepresent invention may be a suspension or a solution.

In a preferred embodiment of the sixth aspect of the present inventionthere is provided a method of improving the aerosolization performanceof a pharmaceutical composition comprising a propellant component and adrug component comprising at least one salmeterol compound selected fromsalmeterol and the pharmaceutically acceptable derivatives thereof, saidmethod comprising using a propellant component comprising1,1-difluoroethane (HFA-152a) and providing a pharmaceutical compositionwhich when delivered from a metered dose inhaler yields a fine particlefraction of the at least one salmeterol compound which is at least 40weight %, preferably at least 42.5 weight % and more preferably at least45 weight % of the emitted dose of the at least one salmeterol compound.

Increasing the fine particle fraction of the emitted dose is highlybeneficial, because it is the fine drug particles that are able topenetrate into the deep bronchiole passages and the alveolar passages ofthe lung to maximise relief from the effects of an asthma attack orCORD.

The fine particle fraction is a widely recognised term in the art. It isa measure of the mass fraction of emitted aerosol particles having adiameter below 5 pm which is generally accepted as being the mostdesirable particle size range for effective alveolar drug delivery.

In the method of the sixth aspect of the present invention suitable andpreferred salmeterol compounds are as described above for thepharmaceutical composition of the first aspect of the present invention.In addition, typical and preferred amounts of the drug component and thepropellant component in the method of the sixth aspect of the presentinvention and suitable, typical and preferred compositions for thepropellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

The drug component in the method of the sixth aspect of the presentinvention may consist essentially of or consist entirely of the at leastone salmeterol compound, such as salmeterol and/or salmeterol xinafoate.By the term “consists essentially of”, we mean that at least 98 weight%, more preferably at least 99 weight % and especially at least 99.9weight % of the drug component consists of the least one salmeterolcompound. Alternatively, the drug component may additionally comprise atleast one long acting muscarinic antagonist and/or at least onecorticosteroid. When a long acting muscarinic antagonist and/orcorticosteroid are included, suitable and preferred long actingmuscarinic antagonists and suitable and preferred corticosteroids are asdescribed above for the pharmaceutical compositions of the second andthird aspects of the present invention.

In one embodiment, the pharmaceutical composition in the sixth aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the drug component and the propellant component asdefined above. By the term “consists essentially of”, we mean that atleast 98 weight %, more preferably at least 99 weight % and especiallyat least 99.9 weight % of the pharmaceutical composition consists of thetwo components.

In an alternative embodiment, the pharmaceutical composition in thesixth aspect of the invention may contain one or both of a polarexcipient and a surfactant component as discussed above for thepharmaceutical composition of the first aspect of the invention.Suitable and preferred polar excipients and surfactants are as discussedabove for the pharmaceutical composition of the first aspect of theinvention. Typical and preferred amounts of the polar excipient and thesurfactant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

In a particularly preferred embodiment of the sixth aspect of thepresent invention, the drug component comprises salmeterol xinafoate andfluticasone propionate and the fine particle fraction of salmeterolxinafoate in the emitted dose when the pharmaceutical composition isdelivered from a metered dose inhaler is at least 40 weight %,preferably at least 42.5 weight % and more preferably at least 45 weight% of the emitted dose of the salmeterol xinafoate. In addition, the fineparticle fraction of fluticasone propionate in the emitted dose when thepharmaceutical composition is delivered from a metered dose inhaler ispreferably at least 33 weight %, more preferably at least 36 weight %and still more preferably at least 39 weight % of the emitted dose ofthe fluticasone propionate.

The pharmaceutical compositions of the invention find particular utilityin the delivery of the salmeterol compounds, and where included thecorticosteroid and long acting muscarinic antagonist compounds, from apressurised aerosol container, e.g. using a metered dose inhaler (MDI).For this application, the pharmaceutical compositions are contained inthe pressurised aerosol container and the HFA-152a propellant functionsto deliver the drug as a fine aerosol spray.

The pharmaceutical compositions of the invention may comprise one ormore other additives of the type that are conventionally used in drugformulations for pressurised MDIs, such as valve lubricants. Where otheradditives are included in the pharmaceutical compositions, they arenormally used in amounts that are conventional in the art.

The pharmaceutical compositions of the invention are normally stored ina pressurised container or canister which is to be used in associationwith a medication delivery device. When so stored, the pharmaceuticalcompositions are normally a liquid. In a preferred embodiment, thepressurised container is designed for use in a metered dose inhaler(MDI). In a particularly preferred embodiment, the pressurised containeris a coated aluminium can or an uncoated aluminium can, especially thelatter.

Accordingly, a seventh aspect of the present invention provides apressurised container holding the pharmaceutical composition of thefirst, second, third or fourth aspect of the present invention. In aneighth aspect, the present invention provides a medication deliverydevice, especially a metered dose inhaler, having a pressurisedcontainer holding the pharmaceutical composition of the first, second,third or fourth aspect of the present invention.

The metered dose inhaler typically comprises a nozzle and valve assemblythat is crimped to a container holding the pharmaceutical composition tobe dispensed. An elastomeric gasket is used to provide a seal betweenthe container and the nozzle/valve assembly. Preferred elastomericgasket materials are EPDM, chlorobutyl, bromobutyl and cycloolefincopolymer rubbers as these can exhibit good compatibility with HFA-152aand also provide a good barrier to prevent or limit HFA-152a permeatingfrom the container.

The pharmaceutical compositions of the present invention are for use inmedicine for treating a patient suffering or likely to suffer from arespiratory disorder and especially asthma or a chronic obstructivepulmonary disease.

Accordingly, the present invention also provides a method for treating apatient suffering or likely to suffer from a respiratory disorder,especially asthma or a chronic obstructive pulmonary disease, whichcomprises administering to the patient a therapeutically orprophylactically effective amount of a pharmaceutical composition asdiscussed above. The pharmaceutical composition is preferably deliveredto the patient using a MDI.

The pharmaceutical compositions of the invention can be prepared and theMDI devices filled using techniques that are standard in the art, suchas pressure filling and cold filling. For example, the pharmaceuticalcompositions can be prepared by a simple blending operation in which theat least one salmeterol compound, optionally the at least onecorticosteroid and/or the at least one long acting muscarinicantagonist, optionally the surfactant component and theHFA-152a-containing propellant are mixed together in the requiredproportions in a suitable mixing vessel. Mixing can be promoted bystirring as is common in the art. Conveniently, the HFA-152a-containingpropellant is liquefied to aid mixing. If the pharmaceutical compositionis made in a separate mixing vessel, it can then be transferred topressurised containers for storage, such as pressurised containers thatare used as part of medication delivery devices and especially MDIs.

The pharmaceutical compositions of the invention can also be preparedwithin the confines of a pressurised container, such as an aerosolcanister or vial, from which the compositions are ultimately released asan aerosol spray using a medication delivery device, such as a MDI. Inthis method, a weighed amount of the at least one salmeterol compoundand optionally the at least one corticosteroid and/or the at least onelong acting muscarinic antagonist, is introduced into the opencontainer. A valve is then crimped onto the container and theHFA-152a-containing propellant component, in liquid form, introducedthrough the valve into the container under pressure, optionally afterfirst evacuating the container through the valve. The surfactantcomponent, if included, can be mixed with the drug(s) or, alternatively,introduced into the container after the valve has been fitted, eitheralone or as a premix with the propellant component. The whole mixturecan then be treated to disperse the drugs in the propellant/surfactantmixture, e.g. by vigorous shaking or using an ultrasonic bath. Suitablecontainers may be made of plastics, metal, e.g. aluminium, or glass.Preferred containers are made of metal, especially aluminium which maybe coated or uncoated. Uncoated aluminium containers are especiallypreferred.

The container may be filled with enough of the pharmaceuticalcomposition to provide for a plurality of dosages. The pressurizedaerosol canisters that are used in MDIs typically contain 50 to 150individual dosages.

The present invention also provides a method of reducing the globalwarming potential (GWP) of a pharmaceutical composition comprising adrug component comprising at least one salmeterol compound selected fromsalmeterol and the pharmaceutically acceptable derivatives thereof,especially the pharmaceutically acceptable salts thereof and apropellant component, said method comprising using a propellantcomponent comprising 1,1-difluoroethane (HFA-152a). This method isapplicable to the preparation of all the pharmaceutical compositionsdisclosed herein in all their aspects and embodiments.

Preferably, at least 90 weight %, more preferably at least 95 weight %and still more preferably at least 99 weight % of the propellantcomponent used is HFA-152a. In an especially preferred embodiment, thepropellant component used is entirely HFA-152a.

The propellant component that is used will preferably have a globalwarming potential (GWP) of less than 250, more preferably less than 200and still more preferably less than 150.

The present invention is now illustrated but not limited by thefollowing examples.

EXAMPLE 1

A number of experiments were conducted to investigate the in vitroaerosolization performance of combination drug formulations ofsalmeterol xinafoate and fluticasone propionate in metered dose inhalers(MDIs) using either HFA-134a or HFA-152a as the propellant.

Pharmaceutical formulations of salmeterol xinafoate and fluticasonepropionate were prepared in either HFA-134a or HFA-152a (Mexichem, UK).The drugs were weighed directly into standard uncoated 14 ml aluminiumcanisters (C128, Presspart, Blackburn, UK). The canisters were thencrimped with a 50 μL valve (Bespak, Kings Lynn, UK) following which thepropellant was filled into the canisters through the valve using amanual Pamasol crimper/filler (Pamasol, Switzerland). Finally, thecanisters were sonicated for 20 minutes to aid dispersion of the drug inthe suspension. The nominal dose of salmeterol xinafoate was 25 μg andthe nominal dose of fluticasone propionate was 125 μg.

High performance liquid chromatography (HPLC) was used to determine drugcontent following aerosolization studies (see below). A 100 mm×4.6 mmAscentis Express 018 column with a 2.7 μm particle size was used for theanalysis. The column was coupled to a UV detector operating at awavelength of 235 and 252 nm. The autosampler was operated at ambienttemperature and 100 μl samples were injected into the column for theanalyses. The chromatographic conditions are shown in Table 1 below.

TABLE 1 UV Pump Flow Wave- Column Rate length Temperature Drug(ml.min⁻¹) Mobile Phase (nm) (° C.) Fluticasone 1.5 Methanol,Acetonitrile 235 40 Propionate and Water 45/35/20% v/v Salmeterol 1.5Methanol, Acetonitrile 252 40 Xinafoate and Water 45/35/20% v/v

The in vitro aerosolization performance of the formulations was studiedusing a Next Generation Impactor (NGI, Copley Scientific, NottinghamUK), which was connected to a vacuum pump (GE Motors, NJ, USA). Prior totesting, the cups of the NGI system were coated with 1% v/v silicone oilin hexane to eliminate particle bounce. For each experiment, threeactuations of the valve were discharged into the NGI at 30 L.min⁻¹ asper pharmacopeia guidelines. Following aerosolization, the NGI apparatuswas dismantled and the actuator and each part of the NGI was washed downinto known volumes of the HPLC mobile phase. The mass of drug depositedon each part of the NGI was determined by HPLC using the methodologydescribed above. This protocol was repeated three times for eachcanister, following which, the fine particle dose (FPD) and fineparticle fraction of the emitted dose (FPFED) were determined. Theresults are shown in Tables 2 and 3 below.

TABLE 2 In vitro aerosolization performance of combination MDIformulations of salmeterol xinafoate and fluticasone propionate inHFA-134a as characterised by the emitted dose, fine particle dose, fineparticle fraction of the emitted dose (FPF_(ED) (%)), mass medianaerodynamic diameter (MMAD) and geometric standard deviation (GSD). Fineparticle Emitted Dose Dose (μg ± Formulation (μg ± S.D.) S.D.) FPF_(ED)(%) MMAD ± GSD Fluticasone 101.7 ± 8.7  31.6 ± 3.3  31.0 3.8 ± 2.5Propionate Saimeterol 22.9 ± 1.3  8.4 ± 0.3 36.7 2.6 ± 2.6 Xinafoate

TABLE 3 In vitro aerosolization performance of combination MDIformulations of salmeterol xinafoate and fluticasone propionate inHFA-152a as characterised by the emitted dose, fine particle dose, fineparticle fraction of the emitted dose (FPF_(ED) (%)), mass medianaerodynamic diameter (MMAD) and geometric standard deviation (GSD). Fineparticle Emitted Dose Dose (μg ± FPF_(ED) (%) Formulation (μg ± S.D.)S.D.) S.D.) MMAD ± GSD Fluticasone 108.7 ± 1.1  43.5 ± 3.4  40.0 2.9 ±2.1 Propionate Salmeterol 18.8 ± 1.6  8.9 ± 0.8 47.2 2.4 ± 2.1 Xinafoate

It is evident from the data presented in Tables 2 and 3 above that thefine particle fractions of the emitted doses upon aerosolization weresignificantly better when HFA-152a was used as the propellant for bothsalmeterol xinafoate and fluticasone propionate.

EXAMPLE 2

The stability of salmeterol xinafoate and fluticasone propionate inHFA-134a and HFA-152a was investigated at time zero (T=0) and afterstorage, valve down, for 1 month (T=1M), 3 months (T=3M) and 6 months(T=6M) at 40° C. and 75% relative humidity (RH) and at 25° C. and 60%relative humidity (RH) in uncoated aluminium cans.

The drug formulations were prepared as described in Example 1 andanalysed using HPLC following the stability studies. A 100 mm×4.6 mmAscentis Express C18 column with a 2.7 μm particle size was used for theanalysis. The column was coupled to a UV detector operating at awavelength of 214 nm. The autosampler was operated at ambienttemperature and 100 μl samples were injected into the column for theanalyses. The chromatographic conditions are shown in Table 4 below.

TABLE 4 UV Column Pump Flow Wave- Temper- Rate length ature Drug(ml.min⁻¹) Mobile Phase (nm) (° C.) Salmeterol 2.0 Mobile Phase A: 25 mM214 60 Xinatoate sodium hydrogen and orthophosphate and Fluticasoneacetonitrile 80:20 v/v Propionate Mobile Phase E3: 25 mM (Dual sodiumhydrogen detection) orthophosphate and acetonitrile 40:60 v/v

The composition of the mobile phase was varied as shown in Table 5below.

TABLE 5 Volume % Time of Mobile Volume % of (mins) Phase A Mobile PhaseB 0 100 0 32.0 0 100 32.1 100 0 37.0 100 0

The results of investigating the chemical stability of the salmeterolxinafoate and fluticasone propionate drug formulations in HFA-152a andHFA-227ea in uncoated aluminium cans are shown, respectively, in Tables6 to 9 below.

TABLE 6 Chemical stability of fluticasone propionate in HFA-134a inuncoated aluminium cans based on percentage assay and total impuritiesupon storage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH, T = 3M@ 40° C./75% RH and 25° C./60% RH and T = 6M @ 40° C./75% RH and 25°C./60% RH. Time % Assay (LC) % total impurities Initial time T = 0 100.8<LoQ T = 1M @ 25/60 100.1 <LoQ T = 1M @ 40/75  99.9 <LoQ T = 3M @ 25/60 99.8 <LoQ T = 3M @ 40/75  99.8 <LoQ T = 6M @ 25/60  97.2 0.32 T = 6M @40/75  96.5 0.48

TABLE 7 Chemical stability of fluticasone propionate in HFA-152a inuncoated aluminium cans based on percentage assay and total impuritiesupon storage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH, T = 3M@ 40° C./75% RH and 25° C./60% RH and T = 6M @ 40° C./75% RH and 25°C./60% RH. Time % Assay (LC) % total impurities Initial time T = 0 100.5<LoQ T = 1M @ 25/60 100.0 <LoQ T = 1M @ 40/75 100.2 <LoQ T = 3M @ 25/6099.8 <LoQ T = 3M @ 40/75 100.0 <LoQ T = 6M @ 25/60 98.9 0.25 T = 6M @40/75 98.6 0.39

TABLE 8 Chemical stability of salmeterol xinafoate in HFA-134a inuncoated aluminium cans based on percentage assay and total impuritiesupon storage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH, T = 3M@ 40° C./75% RH and 25° C./60% RH and T = 6M @ 40° C./75% RH and 25°C./60% RH. Time % Assay (LC) % total impurities Initial time T = 0 99.90.07 T = 1M @ 25/60 99.7 0.08 T = 1M @ 40/75 99.2 0.11 T = 3M @ 25/6098.5 0.18 T = 3M @ 40/75 97.9 0.23 T = 6M @ 25/60 97.5 0.29 T = 6M @40/75 96.9 0.43

TABLE 9 Chemical stability of salmeterol xinafoate in HFA-152a inuncoated aluminium cans based on percentage assay and total impuritiesupon storage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH, T = 3M@ 40° C./75% RH and 25° C. 160% RH and T = 6M @ 40° C./75% RH and 25°C./60% RH. Time % Assay (LC) % total impurities Initial time T = 0 99.90.07 T = 1M @ 25/60 99.9 0.08 T = 1M @ 40/75 99.5 0.08 T = 3M @ 25/6099.6 0.08 T = 3M @ 40/75 99.1 0.11 T = 6M @ 25/60 98.5 0.26 T = 6M @40/75 98.9 0.35

It can be seen from the data in Tables 6 to 9 above that both salmeterolxinafoate and fluticasone propionate exhibit superior chemical stabilitywhen blended with HFA-152a as the aerosolization propellant rather thanHFA-134a.

The invention claimed is:
 1. A pharmaceutical composition comprising: adrug component consisting of salmeterol xinafoate and fluticasonepropionate, and (ii) a propellant component at least 90 wt % of which is1,1-difluoroethane (HFA-152a), wherein the drug component is the soledrug component in the pharmaceutical composition, and wherein thepharmaceutical composition is free of (i) polyvinylpyrrolidone, (ii)polyethylene glycol, (iii) polymers having amide and/or carboxylic acidester repeating structural units.
 2. The pharmaceutical composition ofclaim 1, wherein at least 95% of the propellant component is1,1-difluoroethane (HFA-152a).
 3. The pharmaceutical composition ofclaim 1, wherein at least 99% of the propellant component is1,1-difluoroethane (HFA-152a).
 4. The pharmaceutical composition ofclaim 1, wherein the propellant component is entirely 1,1-difluoroethane(HFA-152a).
 5. The pharmaceutical composition of claim 1, wherein thepropellant component contains from 0.5 to 10 ppm of unsaturatedimpurities.
 6. The pharmaceutical composition of claim 1, furthercomprising a surfactant component comprising at least one surfactantcompound.
 7. The pharmaceutical composition of claim 6, wherein thesurfactant component is free of fluorinated surfactant compounds.
 8. Thepharmaceutical composition of claim 1, further comprising a polarexcipient.
 9. The pharmaceutical composition of claim 8, wherein thepolar excipient is ethanol.
 10. The pharmaceutical composition of claim1, wherein the pharmaceutical composition is free of one or more of thefollowing: (i) perforated microstructures; (ii) acid stabilisers; (iii)pharmaceutically acceptable salts of both cromoglycic acid andnedocromil; (iv) polar excipients; and (v) ethanol.
 11. Thepharmaceutical composition of claim 1, which after storage in uncoatedaluminium containers at 40° C. and 75% relative humidity for 6 monthswill produce less than 0.4% by weight of impurities from the degradationof the at least one salmeterol compound based on the total weight of theat least one salmeterol compound and the impurities.
 12. Thepharmaceutical composition of claim 11, wherein at least 98.0% by weightof the at least one salmeterol compound that is contained originally inthe pharmaceutical composition immediately following preparation will bepresent in the composition after storage in uncoated aluminiumcontainers at 40° C. and 75% relative humidity for 6 months.
 13. Thepharmaceutical composition of claim 1, which when delivered from ametered dose inhaler yields a fine particle fraction of the at least onesalmeterol compound which is at least 42.5 weight % of the emitted doseof the at least one salmeterol compound.
 14. The pharmaceuticalcomposition of claim 1 in the form of a suspension.
 15. Thepharmaceutical composition of claim 6, wherein the pharmaceuticalcomposition comprises a suspension of drug particles and wherein thesurfactant component is not present as a surface coating on thesuspended drug particles.
 16. The pharmaceutical composition of claim 1in the form of a solution.
 17. The pharmaceutical composition of claim1, wherein salmeterol xinafoate is in a micronized form.
 18. Thepharmaceutical composition of claim 1, wherein fluticasone propionate isin a micronized form.
 19. A metered dose inhaler (MDI) fitted with asealed and pressurised aerosol container containing a pharmaceuticalcomposition of claim
 1. 20. A pharmaceutical composition consisting of:(i) a drug component consisting of salmeterol xinafoate and fluticasonepropionate, and (ii) a propellant component at least 90 wt % of which is1,1-difluoroethane (HFA-152a).